Irritable bowel syndrome (IBS) is a common chronic disorder that results in high health care expenditures, disability, and decreased quality of life. Dr. Yuri Ann Saito-Loftus'long term objective is to understand the pathophysiology of this disorder so that better tests and treatments may be discovered. Her K23 Mentored Patient-Oriented Research Career Development Award utilizes a family case-control study design to collect evidence for whether there is a genetic basis for IBS. This application proposes to supplement the K23 study by accomplishing two additional specific aims using data and DNA collected from the K23 study. Because serotonin and serotonin-related proteins have been implicated in the pathophysiology of IBS, we propose performing a pathway-based candidate-gene association study to determine whether genetic variants in genes encoding serotonin-related molecules are associated with IBS. Using our institution's high-throughput genotyping resources, 384 linkage disequilibrium (LD) tag SNPs in 22 serotonin pathway genes will be genotyped in 645 cases and 323 controls, and IBS subgroups will be analyzed to determine whether there is evidence for genetic heterogeneity for this clinically heterogeneous disorder. A candidate gene association study of this type and scale has not been performed to date and could provide specific genes and molecular targets for future study. PUBLIC HEALTH RELEVANCE Irritable bowel syndrome (IBS) is a common chronic disorder that results in high health care expenditures and disability because the underlying mechanism is unknown. The broad objective of this study is to identify specific genes and molecular targets for future study so that better tests and treatments may be developed. With this study, we propose using collected DNA and our institution's high-throughput genotyping resource to study the genome to determine whether there are regions that may contain genetic variants or mutations responsible for IBS.